IntroductionThe availability of accurate, repeatable and quick time response measurements is The availability of accurate, repeatable and quick time response measurements is necessary for an arterial blood pressure monitoring system (Valerio et al. 2006). necessary for an arterial blood pressure monitoring system (Valerio et al. 2006). Currently, approaches for accurate blood pressure determination rely predominantly on invasive techniques. However, chronic toxicologic studies in cynomolgus monkeys require non-invasive methods that should meet all stated necessities and are applicable for a large number of animals and day-by-day routines. The present work evaluates the high-definition oscillometry (HDO) technique as a potential non-invasive approach for accurate blood pressure recordings in cynomolgus monkeys. HDO enables visible, real-time control of each measurement on a screen by the use of blood pressure amplitude scans with up to 16.000 Hz within 10-15 sec (Figures 1 and 2).

Animals, Material and MethodsEighteen adult cynomolgus monkeys (12 males, 6 females) were used in this study. Mean body weight was 7.3 kg (males) and 3.8 kg (females). Six male cynomolgus monkeys chronically implanted with telemetry transmitters were used for simultaneous telemetric and HDO measurements. HDO was performed by Memo Diagnostic (MD) 1.35.00 (S+B medVet GmbH, Babenhausen, Germany).

Monitoring in Conscious AnimalsThe animal was restrained in a prone position with the blood pressure cuff fixed on the animal’s right upper arm. After an adaptation period, the measurements were started and resulted in values for systolic (SYS), diastolic (DIA), mean arterial blood pressure (MAP) and pulse rate per min. In conscious, nontelemeterized animals, these parameters were determined 15 times for each animal in one session and resulted in an average value for each individual for each parameter. In the two following days, this procedure was repeated.

Monitoring During AnesthesiaAll females were measured by HDO every minute under two anesthetic regimens: Ketamine (10 mg/kg BW) and Ketamine-Xylazine (Ketamine 10 mg/kg BW, Xylazine 0.3-0.7 mg/kg BW). Furthermore, the six implanted males (Koenigsberg T27 cardiovascular transmitter (DISS, Dexter, USA)) were measured simultaneously by HDO and telemetry technique every minute. These males were anesthetized after 4 to 10 minutes of interval measurements by Ketamine-Xylazine i.m. injection (Ketamine 10 mg/kg BW, Xylazine 0.25-0.3 mg/kg BW). Statistical analyses were performed by the use of SigmaPlot 9.0 and SAS 8.2 with appropriate tests, all with two-sided risk. A P value of P value of P< 0.05 was considered significant.

ResultsWhen BP was determined the first time, the HDO measurements detected significant differences between males and females due to a significantly elevated BP in males being first-time restrained (Figure 3). This significant sex difference disappeared in the consecutive days of measurement and resulted in an average MAP of 96 mm Hg for males and 87 mm Hg for females at day 3.

Both telemetry and HDO revealed a nearly twofold decrease of heart rate under Ketamine-Xylazine anesthesia (Figure 4). Data for pulse rate were comparable whereas data for MAP were consistently higher and more variable in telemeterized animals when compared to HDO measurements (Figure 5). Twenty five ± 2 minutes after dosing, a comparable and significant reduction of MAP compared to predose values was detected by both approaches (HDO: Delta mm Hg: 41 ± 7; telemetry: Delta mm Hg: 49± 11). However, in absolute values, the variability in telemeterized animals was clearly higher compared to HDO (Figure 6): Whereas the MAP during anesthesia for telemetry recordings ranged between 45 and 105 mm Hg, HDO yielded lower variation from 57 to 77 mm Hg. Data are summarized in Table 1.

Non-invasive Blood Pressure Monitoring in the Cynomolgus Monkey (Macaca fascicularis): High-Definition Oscillometry versus Implanted Telemetric DevicesBarthel Schmelting1, Marc Niehoff1, Beate Egner2, Sven H. Korte1 and Gerhard Weinbauer11Covance Laboratories, Münster, Germany; 2S+B medVet GmbH, Babenhausen, Germany

DiscussionAs gold standard for blood pressure measurement, direct invasive techniques are seen although they have variable degrees of invasivity (Valerio et al. 2006). Literature review for blood pressure values in macaques (Table 2) may lead to the same assumption since standard deviations in direct measurements are very narrow in regard to ordinary oscillometry. However, our own results gained by non-invasive HDO (Table 1) show a comparable tight standard deviation like in direct techniques. The elevated MAP in first-time restrained animals might be traced back to the excitement of the adult and fully mature males not yet used to the procedure. Same as implanted telemetry, HDO is able to detect drug-related cardiovascular changes. The limited variation in our study reflects the high reproducibility, feasibility and accuracy of blood pressure measurement in M. fascicularis by HDO even in conscious animals.

Conclusions■ HDO provides the ability and accuracy to detect drug-related cardiovascular changes

non-invasively.

■ HDO generates data that correspond to those gained by invasive techniques and are applicable for large number of animals and day-by-day routines.

■ HDO may be regarded as an alternative for invasive surgeries in macaques used as an animal model for cardiovascular research.

LiteratureAsai K, Kudej RK, Shen YT, Yang GP, Takagi G, Kudej AB, Geng YJ, Sato N, Nazareno JB, Vatner DE, Natividad F, Bishop SP, Vatner SF. 2000. Arterioscler Thromb Vasc Biol. 20(6):1493-9.Chester AE, Dorr AE, Lund KR, Wood LD 1992. Fund Appl Toxicol 19, 64-68.Fund Appl Toxicol 19, 64-68.Fund Appl ToxicolGatecel C, Losser MR, Payen D 2003. Anesth Analg. 96(3):740-5.Hotchkiss CE, Wang C, Slikker W 2007. JAALAS 46(6):21-28. JAALAS 46(6):21-28. JAALASMiyazaki M, Sakonjo H, Takai S 1999. Br J Pharmacol. 128(3):523–529.Saywer DC, Guikema AH, Siegel EM 2004. Vet Anaest Analgesia 31:27-39.Valerio F, Mariscoli M, Petrizzi 2006. Vet Res Communicat. 30(Suppl1):321-323.

Figure 1. Screenshot of a conscious animal (Systolic BP 138 mm Hg, diastolic BP 88 mm Hg, Pulse 239 bpm).

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Figure 4. Pulse rate during Ketamine-Xylazine anesthesia (induction at T0) in males (N=6) measured by telemetry and HDO.

Figure 5. MAP during Ketamine-Xylazine anesthesia (induction at T0) in males (N=6) measured by telemetry and HDO.

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Figure 6. Drug related cardiovascular changes: MAP predose (1 & 3) and 25 min after anesthesia induction (2 & 4), determined by telemetry (1 & 2) and HDO (3 & 4).

Table 1. MAP in M. fascicularis – Own Results, Differentiated by MethodM. fascicularis – Own Results, Differentiated by MethodM. fascicularis

Table 2. MAP in Macaques – Literary Review

Figure 2. Screenshot of the same animal 25 min after Ketamine-Xylazine injection (Systolic BP 78 mm Hg, diastolic BP 49 mm Hg, Pulse 132 bpm).

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Presented at the47th Annual Society of ToxicologyMeeting and ToxExpo™Seattle, Washington16–20 March 2008

Non-invasive Blood Pressure Monitoring in the Cynomolgus Monkey (Macaca fascicularis): High-Definition Oscillometry versus Implanted Telemetric Devices

Barthel Schmelting1, Marc Niehoff1, Beate Egner2, Sven H. Korte1

and Gerhard Weinbauer11Covance Laboratories, Münster, Germany2S+B medVet GmbH, Babenhausen, Germany

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